The invention relates generally to the use of sesquiterpene lactones in the treatment of infections caused by Flaviviridae and, more specifically, to the use of sesquiterpene lactone endoperoxides to treat hepatitis C infections, yellow fever, dengue fever, bovine viral diarrhea and classical swine fever.
Chronic hepatitis C infection is a substantial public health problem affecting 180 million people worldwide (3% of the population), including 4 million people in the United States and is a leading cause of chronic liver disease. It is predicted that HCV infection will continue to rise in the U.S. with three times as many people infected by the year 2010. Infection with the hepatitis C virus may lead to an increased probability of developing serious and, in some cases, life threatening chronic liver disease including liver failure and cancer.
Chronic liver disease is the tenth leading cause of death among adults in the United States, and accounts for approximately 25,000 deaths annually, or approximately 1% of all deaths. Population-based studies indicate that 40% of chronic liver disease is HCV-related, resulting in an estimated 8,000-10,000 deaths each year. Current estimates of medical and work-loss costs of HCV-related acute and chronic liver disease are greater than $600 million annually, and HCV-associated end-stage liver disease is the most frequent indication for liver transplantation among adults. Because most HCV-infected persons are aged 30-49 years, the number of deaths attributable to HCV-related chronic liver disease could increase substantially during the next 10-20 years as this group of infected people reaches ages at which complications from chronic liver disease typically occur.
HCV is transmitted primarily through large or repeated direct percutaneous exposures to blood. In the United States, the two most common exposures associated with transmission of HCV are blood transfusion and injecting-drug use. Therapy for hepatitis C is a rapidly changing area of clinical practice. Combination therapy with interferon and ribavirin, a nucleoside analogue, is approved for the naive treatment of patients with chronic hepatitis C. Studies of patients treated with a combination of ribavirin and interferon have demonstrated a substantial increase in sustained response rates, reaching 40%-50%, compared with response rates of 15%-25% with interferon alone. Most patients receiving interferon experience flu-like symptoms early in the treatment, but these symptoms diminish with continued treatment. Later side effects include fatigue, bone marrow suppression and neuropsychiatric effects (e.g. apathy, cognitive changes, irritability and depression). Interferon dosage must be reduced in 10%-40% of patients and discontinued in 5%-15% because of severe side effects. Ribavirin can induce hemolytic anemia and can be problematic for patients with pre-existing anemia, bone marrow suppression or renal failure. In these patients, combination therapy should be avoided or attempts should be made to correct the anemia. Hemolytic anemia caused by ribavirin also can be life-threatening for patients with ischemic heart disease or cerebral vascular disease. Ribavirin is teratogenic, and female patients should avoid becoming pregnant during therapy. Other treatments, including corticosteroids, ursodiol and thymosin, have not been effective. High iron levels in the liver might reduce the efficacy of interferon. Use of iron reduction therapy (phlebotomy or chelation) in combination with interferon has been studied, but results have been inconclusive (www.cdc.gov). Therefore, a strong medical need exists to discover and develop new bioactive molecules that can be used to treat hepatitis C infections with fewer or reduced side effects and better efficiency compared to the current available treatments.